scholarly journals Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

2021 ◽  
Author(s):  
zhen lin ◽  
libin ni ◽  
cheng teng ◽  
zhao zhang ◽  
xinlei lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Oxidative Damage ◽  
Er Stress ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Cellular Damage ◽  
Nucleus Pulposus Cells

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD.

scholarly journals Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

2019 ◽  
Vol 2019 ◽  
pp. 1-27 ◽  
Author(s):  
Liang Kang ◽  
Qian Xiang ◽  
Shengfeng Zhan ◽  
Yu Song ◽  
Kun Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Disc Degeneration ◽  
Cell Apoptosis ◽  
Intervertebral Disc Degeneration ◽  
Autophagic Flux ◽  
Ecm Degradation

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

Therapeutic Potential of Naringin for Intervertebral Disc Degeneration: Involvement of Autophagy Against Oxidative Stress-Induced Apoptosis in Nucleus Pulposus Cells

2018 ◽  
Vol 46 (07) ◽  
pp. 1561-1580 ◽  
Author(s):  
Zengjie Zhang ◽  
Chenggui Wang ◽  
Jialiang Lin ◽  
Haiming Jin ◽  
Ke Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Therapeutic Potential ◽  
Nucleus Pulposus Cells ◽  
Induced Apoptosis

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but few efficacious medicines have been developed for IDD. Increased nucleus pulposus cells apoptosis is a dominant pathogenesis of IDD and is considered a therapeutic target. Previously, our group proved that autophagy may protect nucleus pulposus cells against apoptosis. As one of the major bioflavonoids of citrus, naringin activates autophagy. Therefore, we hypothesize that naringin may have therapeutic potential for IDD by activating autophagy in nucleus pulposus cells. In this study, we evaluated the effects of naringin on TBHP-induced oxidative stress in nucleus pulposus cells in vitro as well as in puncture-induced rat IDD model in vivo. Our results showed that naringin could reduce the incidence of oxidative stress-induced apoptosis in nucleus pulposus cells and promoted the expression of autophagy markers LC3-II/I and beclin-1. Meanwhile, inhibition of autophagy by 3-MA may partially reverse the anti-apoptotic effect of naringin, indicating that autophagy was involved in the protective effect of naringin in nucleus pulposus cells. Further study showed that autophagy regulation of naringin may be related to AMPK signaling. Also, we found that naringin treatment can regulate the expression of collagen II, aggrecan and Mmp13 to sustain the extracellular matrix. Furthermore, our in vivo study showed that naringin can ameliorate IDD in puncture-induced rat model. In conclusion, our study suggests that naringin can protect nucleus pulposus cells against apoptosis and ameliorate IDD in vivo, the mechanism may relate to its autophagy regulation.

scholarly journals The Potential Role of Extensor Muscle Fatigue in the Onset of Intervertebral Disc Degeneration: A Novel In Vivo Model

2010 ◽  
Vol 10 (9) ◽  
pp. S74-S75
Author(s):  
Mary Beth M. Grabowsky ◽  
Nicholas A. Pallotta ◽  
Matthew W. Connelly ◽  
Brett Van Etten ◽  
Rebecca A. MacDonald ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Muscle Fatigue ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Potential Role ◽  
Extensor Muscle ◽  
In Vivo Model

scholarly journals Mechanosensitive Ion Channel Piezo1 Activated by Matrix Stiffness Regulates Oxidative Stress-Induced Senescence and Apoptosis in Human Intervertebral Disc Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-13 ◽  
Author(s):  
Bingjin Wang ◽  
Wencan Ke ◽  
Kun Wang ◽  
Gaocai Li ◽  
Liang Ma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Ion Channel ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Elasticity Modulus ◽  
Mechanosensitive Ion Channel ◽  
Mechanical Transduction ◽  
Crucial Part

Mechanical stimulation plays a crucial part in the development of intervertebral disc degeneration (IDD). Extracellular matrix (ECM) stiffness, which is a crucial mechanical microenvironment of the nucleus pulposus (NP) tissue, contributes to the pathogenesis of IDD. The mechanosensitive ion channel Piezo1 mediates mechanical transduction. This study purposed to investigate the function of Piezo1 in human NP cells under ECM stiffness. The expression of Piezo1 and the ECM elasticity modulus increased in degenerative NP tissues. Stiff ECM activated the Piezo1 channel and increased intracellular Ca2+ levels. Moreover, the activation of Piezo1 increased intracellular reactive oxygen species (ROS) levels and the expression of GRP78 and CHOP, which contribute to oxidative stress and endoplasmic reticulum (ER) stress. Furthermore, stiff ECM aggravated oxidative stress-induced senescence and apoptosis in human NP cells. Piezo1 inhibition alleviated oxidative stress-induced senescence and apoptosis, caused by the increase in ECM stiffness. Finally, Piezo1 silencing ameliorated IDD in an in vivo rat model and decreased the elasticity modulus of rat NP tissues. In conclusion, we identified the mechanosensitive ion channel Piezo1 in human NP cells as a mechanical transduction mediator for stiff ECM stimulation. Our results provide novel insights into the mechanism of mechanical transduction in NP cells, with potential for treating IDD.

scholarly journals Protective Effect of Polygonatum sibiricum Polysaccharides on Apoptosis, Inflammation, and Oxidative Stress in Nucleus Pulposus Cells of Rats with the Degeneration of the Intervertebral Disc

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Zhaohui Zhai ◽  
Zhaoxin Li ◽  
Zhonglei Ji ◽  
Xiaosheng Lu
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Rat Model ◽  
Intervertebral Disc Degeneration ◽  
Intervertebral Discs ◽  
New Drugs ◽  
Nucleus Pulposus Cells ◽  
And Oxidative Stress

Objective. Polygonatum sibiricum polysaccharide (PSP) has antioxidant activity, immune enhancement, and other biological properties. However, the effect of PSP on intervertebral disc degeneration has not been reported. In this study, we mainly investigated the effect of PSP on the apoptosis, inflammation, and oxidative stress of nucleus pulposus cells (NPCs) during the process of intervertebral disc degeneration. Methods. A rat NPC model induced by H2O2 was constructed. The CCK8 method was used to measure the effects of PSP on the apoptosis of rat NPCs induced by H2O2. The effects on the activity of SOD and content of MDA were also determined. The rat model of intervertebral disc degeneration was treated with PSP for 1 month, and the mRNA expression levels of IL-1β, COX2, iNOS, Col2α1, Col10α1, and MMP3 were measured by qPCR in the tissue of intervertebral disc. NPCs from the degenerated intervertebral discs were separated, and the cell viability was measured by the CCK8 method. The contents of SOD and MDA in NPCs were determined as well. Results. PSP significantly reduced the apoptosis of NPCs induced by H2O2, significantly increased the SOD content, and decreased the content of MDA in H2O2-induced NPCs. The expression level of IL-1β, COX2, and iNOS in the rat model with intervertebral disc degeneration was significantly downregulated after 1 month of PSP treatment. PSP treatment increased the expression of Col2α1 type and significantly decreased the expression of Col10α1 type collagen and MMP3 in rats with disc degeneration. PSP treatment significantly reduced NPC apoptosis and increased its SOD content and reduced MDA content, which is consistent with the results from cell-level experiments. Conclusion. PSP can effectively reduce the apoptosis, inflammation, and oxidative stress of H2O2-induced NPCs in rats with intervertebral disc degeneration and mitigate the progression of intervertebral disc degeneration, which has the potential to be developed as new drugs for the treatment of intervertebral disc degeneration.

Exosomes derived from human placental MSCs carrying miR-4450 inhibitor alleviate intervertebral disc degeneration and ameliorate gait disturbances via up-regulation of ZNF121

2020 ◽  
Author(s):  
Qiling Yuan ◽  
Xinyi Wang ◽  
Liang Liu ◽  
Yongsong Cai ◽  
Xiaoming Zhao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Therapeutic Effects ◽  
Nucleus Pulposus Cells ◽  
Gait Abnormality ◽  
Tnf Α ◽  
Potential Therapeutic Role

Abstract Background Exosomes derived from mesenchymal stem cells (MSCs) have emerged as novel drug and gene delivery tools. Current study aimed to elucidate the potential therapeutic role of human placental MSC (hPLMSC)-derived exosomes carrying antagomiR-4450 (EXO-antagomiR-4450) in intervertebral disc degeneration (IDD) progression. Methods Initially, the differentially expressed miRNAs related to IDD were identified by microarray analysis which provided data predicting the interaction between miR-4450 and ZNF121 in IDD. Next, miR-4450 and ZNF121 were elevated or silenced to determine their effects on the damage of NPCs treated with TNF-α. The therapeutic effects of EXO-antagomiR-4450 on nucleus pulposus cells (NPCs) were verified both in vitro and in vivo, especially gait analysis and fluorescent molecular tomopraphy were used in live IDD mice. Results Our results revealed that miR-4450 was highly expressed, while ZNF121 was poorly expressed in IDD patients and NPCs treated with TNF-α. Furthermore, miR-4450 was identified to specifically target ZNF121. Additionally, the inhibition of miR-4450 exerted an alleviatory effect on the inflammation, apoptosis and damage of the NPCs by up-regulating ZNF121. Moreover, EXO-antagomiR-4450 retarded damage of NPCs in vitro, alleviated IDD damage and ameliorated gait abnormality in vivo. Conclusion hPLMSC-derived exosomes could be a feasible nanovehicle to deliver inhibitory oligonucleotides like antagomiR-4450 in IDD.

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